Primary biliary cholangitis

Etiology

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• PBC is considered an autoimmune disease
• Often associated with other autoimmune conditions, e.g.:
  • CREST syndrome
  • Sicca syndrome
  • Autoimmune thyroid disease, especially Hashimoto thyroiditis
  • Celiac disease
  • Rheumatoid arthritis

Pathophysiology

Inflammation and progressive destruction (likely due to an autoimmune reaction) of the small and medium-sized intrahepatic bile ducts (progressive ductopenia) → defective bile duct regeneration → chronic cholestasis → secondary hepatocyte damage due to increased concentration of toxins that typically get excreted via bile → gradual portal and periportal fibrotic changes → liver failure → liver cirrhosis and portal hypertension (in advanced stage)

Clinical features

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Clinical features of PBC

Similar to PSC + xanthomas and xanthelasma

Patients with PBC are usually initially asymptomatic.

• Fatigue: most common and often the first symptom
• Marked pruritus: generalized
• Symptoms of cholestasis
  • Jaundice
  • Pale stool, dark urine
  • Maldigestion (more common in advanced disease)
    • Deficiency of fat-soluble vitamins (A, D, E, and K)
• Signs of cirrhosis and portal hypertension
  • Hepatomegaly with dull lower margin, RUQ discomfort
  • Splenomegaly
• Hyperpigmentation
  • Due to increased amounts of melanin; the exact cause and pathomechanism remain unclear.
• Xanthomas and xanthelasma

Diagnostics

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Autoimmune Liver Diseases

Feature	Primary Sclerosing Cholangitis (PSC)	Primary Biliary Cholangitis (PBC)	Autoimmune Hepatitis (AIH)
Patho	Inflammation/fibrosis of intra- & extrahepatic bile ducts	Autoimmune destruction of intrahepatic bile ducts	Autoimmune destruction of hepatocytes
Epi / Assoc.	M > F (2:1), <40s Assoc: Ulcerative Colitis (IBD) (>80%)	F >> M (9:1), 40-60s Assoc: Sjögren’s, other autoimmune dz	F > M (3:1), bimodal (young/middle-aged) Assoc: Other autoimmune dz
Labs	Cholestatic: ↑↑ ALP, ↑ GGT	Cholestatic: ↑↑ ALP, ↑ GGT	Hepatocellular: ↑↑↑ AST/ALT (>1000s common), ↑ IgG
Serology	(+) p-ANCA	(+) AMA (Anti-Mitochondrial Ab)	(+) ANA, (+) ASMA (Anti-Smooth Muscle Ab)
Dx / Histo	MRCP/ERCP: “Beads on a string” Histo: “Onion skinning” periductal fibrosis	Normal imaging Histo: Florid duct lesion (lymphocytic cholangitis, granulomas)	Normal/nonspecific imaging Histo: Interface hepatitis, plasma cells
Tx	Symptomatic Tx; Liver transplant (definitive)	Ursodeoxycholic acid (UDCA)	Corticosteroids, Azathioprine
Key Risk	Cholangiocarcinoma, Colorectal Cancer (w/ UC)	Osteoporosis, Cirrhosis, HCC	Cirrhosis, Acute Liver Failure

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• Liver chemistries: cholestatic pattern of injury
  • ↑ ALP, ↑ GGT, ↑ direct bilirubin
  • Mild transaminitis (or normal AST and ALT)
• Lipid panel: hypercholesterolemia
• PBC-specific autoantibodies
  • Antimitochondrial antibodies (AMA) (present in > 95% of patients)
• Immunoglobulins (nonspecific)
  • ↑ IgM
• Biopsy
  • Because intrahepatic bile ducts are concentrated in the periportal regions, histopathology demonstrates periductal fibrosis predominantly in those regions.

Treatment

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General principles

• Start pharmacotherapy with ursodeoxycholic acid for all patients.
• Offer supportive care, including management of cholestasis-associated pruritus.
• Liver transplantation is necessary if liver cirrhosis is advanced.

Pharmacotherapy

• First-line: ursodeoxycholic acid (UDCA, ursodiol): a hydrophilic, nontoxic bile acid with immunomodulatory, anti-inflammatory, choleretic, and cytoprotective effects
  • Slows disease progression and development of complications (e.g., esophageal varices)
  • Prolongs transplant-free and overall survival
  • Also used in primary sclerosing cholangitis, cholestasis of pregnancy, and small cholesterol stones